Derivatives of 3, 4-dihydro-2h-1, 2, 4-benzothiadiazine-1, 1-dioxide



United States Patent 3,351,595 DERIVATIVES 0F 3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE George de Stevens and Lincoln HarveyWerner, Summit, N.J., assignors to Ciha Corporation, New York, N.Y., acorporation of Delaware No Drawing. Filed Dec. 7, 1962, Ser. No. 242,913The portion of the term of the patent subsequent to Dec. 29, 1981, hasbeen disclaimed 17 Claims. (Cl. 260243) This application is acontinuation-in-part of our application Serial No. 12,679, filed March4, 1960, now abandoned, which is in turn a continuation-in-part of ourapplication Serial No. 855,275, filed November 25, 1959, now abandoned,which in turn is a continuation-in-part of our application Serial No.791,044, filed February 4, 1959, now abandoned, which in turn is acontinuationin-part of our application Serial No. 764,482, filedSeptember 29, 1958, now abandoned, which in turn is acontinuation-in-part of our application Serial No. 751,620, filed July29, 1958, and now abandoned, which in turn is a continuation-in-part ofour application Serial No. 740,- 582, filed June 9, 1958, and nowabandoned, which in turn is a continuation-in-part of our applicationSerial No. 727,242, filed April 9, 1958, and now abandoned. Thisapplication is also a continuation-in-part of our application Serial No.42,216, filed July 12, 1960, now abandoned.

The present invention concerns 3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxide compounds. More particularly, it relates tothe compounds of the formula in which R represents an aliphaticcarbocyclic hydrocarbon or an aliphatic carbocyclic hydrocarbon-loweraliphatic hydrocarbon radical, each of the radicals R and R stands forhydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon orcarbocyclic aryl-lower aliphatic hydrocarbon, R represents hydrogen orlower alkyl, and R represents lower alkyl, halogeno-lower alkyl orhalogen, or alkali met-a1 salts thereof, as well as process for thepreparation of such compounds.

Aliphatic carbocyclic hydrocarbon radicals R are radicals, in which thealiphatic carbocyclic (alicyclic) portion may be saturated or maycontain one or more than one double bond depending on the number or ringcarbon atoms. cycloalkyl may contain from three to eight, especiallyfrom five to six, and cycloalkenyl from four to eight, particularly fromfive to six, ring carbon atoms. Cycloalkyl may be represented bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl, Whereas cycloalkenyl radicals may be, for example, 2-cyclo'butenyl, 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl,3-cyclohexenyl, 3-cycloheptenyl, 2-cyclo-octenyl and the like.

Aliphatic carbocyclic hydrocarbon-lower aliphatic hydrocarbon radicalsare primarily carbocyclic aliphatic hydrocarbon-lower alkyl radicals, inwhich the aliphatic carbocyclic (alicyclic) portion may be saturated orcontain one or more than one double bond depending on the number of ringcarbon atoms, which may 'be from three to eight, and in which loweralkyl is represented by a lower alkylene radical containing from one toseven, such as from one to four, especially from one to two, carbonatoms, e.g. methylene, l,1-ethylene, 1,2-ethylene, as well asl,l-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,4-butyleneand the like.

3,351,595 Patented Nov. 7, 1967 Such radicals are particularlycycloalkyl-lower alkyl radicals, in which cycloalkyl contains from threeto eight, especially from five to six, ring carbon atoms and lower alkylcontains from One to four carbon atoms, especially cycloalkylmethyl, inwhich cycloalkyl contains from three to eight, primarily from five tosix, ring carbon atoms, e.g. cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclo-octylmethyl and the like, l-cycloalkylethyl, in which cycloalkylcontains from three to eight, particularly from five to six, ring carbonatoms, e.g. l-cyclopropylethyl, l-cyclobutylethyl, l-cyclopentylethyl,l-cyclohexylethyl, l-cycloheptylethyl and the like, or2-cycloa1kyl-ethyl, in which cycloalkyl contains from three to eight,particularly from five to six, ring carbon atoms, e.g.2-cyclopropylethyl, Z-cyclopentylethyl, 2-cyclohexylethyl,2-cycloheptylethyl and the like, as well as other cycloalkyl-lower alkylradicals, in which cycloalkyl contains from three to eight, particularlyfrom five to six, ring carbon atoms and lower alkyl contains from threeto four carbon atoms, e.g. l cyclopentylpropyl, 2-cyclopentylpropyl,3-cyclopentylpropyl, 4-cyclopentylbutyl, l-cyclohexylpropyl, 2-cyclohexylpropyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl and the like.

Cycloalkenyl-l-ower alkyl radicals, in which cycloalkenyl contains fromfour to eight, especially from five to six, ring carbon atoms and loweralkyl contains from one to four carbon atoms, are primarilycycloalkenyl-methyl, in which cycloalkenyl contains from four to eight,particularly from five to six, ring carbon atoms, e.g.2-cyclopentenylmethyl, 3cyclopentenylmethyl, 2-cyclohexenyl methyl,3-cyclohexenylmethyl and the like, l-cycloalkenyl-ethyl, in whichcycloalkenyl contains from four to eight, particularly from five to six,ring carbon atoms, e.g. l-(2-cyclopentenyl)-ethyl,l-(3-cyclopentenyl)-ethyl, 1-(2 cyclohexenyl)-ethyl,l-(3-cyclohexenyl)-ethyl and the like, or 2-cycloalkenyl-ethyl, in whichcycloalkenyl contains from four to eight, particularly from five to six,carbon atoms, e.g. 2-(2-cyclopentenyl)-ethyl, 2-(3--cyclopentenyl)-ethyl, 2 (2 cyclohexenyl)ethyl, 2-(3-cyclohexenyl)-ethyl and the like, as well as other cycloalkenyl-loweralkyl, in which cycloalkenyl contains from four to eight, especiallyfrom five to six, ring carbon atoms and lower alkyl contains from threeto four carbon atoms, e.g. 1-(Z-cyclopentenyl)-propyl,l-(3-cyclopentenyl -propyl, 2- 2-cyclopentenyl) -propyl, 2- 3-cyclopentenyl)-propyl, 3 (3 cyclopentenyl)-propyl,4-(3-cyclopentenyD-butyl, 1-(2-cyclohexenyl)-propyl,1-(3-cyclohexenyl)-pro-pyl, 2-(3-cyclohexenyl)-propyl,3(3-cyclohexenyD-propyl, 4-(3-cyclohexenyl)-butyl and the like.

The above-mentioned carbocyclic alicyclic hydrocarbon radicals arepreferably unsubstituted; substituents are, for example, lower alkyl,e.g. methyl, ethyl and the like, hydroxyl, etherified hydroxyl, such aslower alkoxy, e.g. methoxy, ethoxy and the like, esterified hydroxyl,such as lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy,ethoxycarbonyloxy and the like, lower alkanoyloxy, e.g. acetoxy,propionoxy and the like, or halogeno, e.g. fiuoro, chloro, bromo and thelike, etheri-fied mercapto, such as lower alkyl-mercapto, e.g.methylmercapto, ethylmercapto and the like, or amino, such asunsubstituted amino, N-monosubstituted amino, for example, N-loweralkyl-amino, e.g. N-methyl-amino, N-ethyl-amino and the like, orN,N-disubstituted amino, for example, N,N- di-lower alkyl-amino, e.g.N,N-dimethylamino, N,N-diethylamino, or N,N-lower alkylene-imino, e.g.l-pyrrolidino, 1-piperidino and the like.

The radicals R and R represent primarily hydrogen; they may also standfor lower alkyl containing from one to four carbon atoms, e.g. methyl,ethyl, n-propyl, isopropyl and the like, lower alkenyl, particularlyallylic lower alkenyl containing from three to five carbon atoms e.g.Z-propenyl (allyl), 2-methyl-2-propenyl (Z-methylallyl), Z-butenyl(3-methyl-allyl) and the like, or monocyclic carbocyclic aryl-loweralkyl, particularly phenyllower alkyl, in which lower alkyl containsfrom one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyland the like. These groups may carry additional substituents, such aslower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g.methoxy, ethoxy and the like, lower alkyl-mercapto, e.g. methylmercapto,e-thylmercapto and the like, halogeno, e.g. fiuoro, chloro, bromo andthe like.

The radical R represents primarily hydrogen; lower alkyl substituentsmay be, for example, methyl, ethyl and the like.

The substituent R in the 6-position of the 3,4-dihydro-2H-1,2,4-benzothia-diazine-l,l-dioxides of this invention representsprimarily halogeno, such as fiuoro, bromo or particularly chloro. Othersubstituents are, for example, lower alkyl, e.g. methyl, or, moreadvantageously, halogeno-lower alkyl, e.g. trifluo-romethyl and thelike.

An alkali metal salt is particularly a sodium or a potassium salt.

The 3,4 dihydro-ZH-l,2,4-benzothiadiazine-l,l-dioxide compounds of thisinvention have diuretic and natriuretic properties and can be used asdiuretic and natriutetic agents with improved properties, such as, forexample, a favorable sodium: potassium excretion ratio, to relievestates of excessive water and sodium retention, as for example,connected with heart troubles. In addition, these compounds haveantihypertensive properties, which can be utilized in the treatment ofhypertensive conditions, such as renal hypertension and the like.

Particularly useful as diuretic and natriuretic agents are the compoundsof the formula in which R represents cycloalkyl containing from three toeight, particularly from five to six, ring carbon atoms, and R standsfor halogeno or trifluoromethyl, or the alkali metal salts of suchcompounds. This group may be represented by the compounds of the formula(g2 rnNozs R3 (I3M (cycloalkyl) in which cycloalkyl contains from fiveto six ring carbon atoms and R stands for chloro or trifiuoromethyl.

An additional group of highly active compounds are those of the formula(52 HzNOzS- I (DH-R1 R in which R represents cycloalkenyl, containingfrom four to eight, particularly from five to six, ring carbon atoms,and R stands for halogeno or trifluoromethyl, or the alkali metal saltsof such compounds. This group may be represented by the compounds of theformula in which cycloalkenyl contains from five to six ring carbonatoms and R represents chloro or trifluorornethyl.

Another group of compounds exerting particularly useful diuretic andantihypertensive effects, coupled with improved properties, are thecompounds of the formula in which R stands for cycloalkyl-lower alkyl,in which cycloalkyl contains from three to eight, particularly from fiveto six, ring carbon atoms, and lower alkyl contains from one to four,particularly from one to two, carbon atoms and R represents halogeno ortrifluoromethyl, or the alkali metal salts of such compounds. This groupmay be represented by the compounds of the formulae in which cycloalkylcontains from five to six ring carbon atoms and R stands for chloro ortrifluoromethyl.

A further group of compounds showing useful diuretic andantihypertensive effects are the compounds of the formula 1 OH-CH-(cycloalkenyl) H CH HzNOgS CH-C HzGHr-(eycloalkenyl) in whichcycloalkenyl contains from five to six ring carbon atoms and R standsfor chloro or trifiuoromethyl. The new compounds of this invention maybe used as medicaments in the form of pharmaceutical preparations,

which contain the new 3,4-dihydro-2H-1,2,4-benzothiadiazine-l,1-dioxidesor the salts thereof in admixture with a pharmaceutical organic orinorganic, solid or liquid carrier suitable for enteral, e.g. oral, orparenteral administration. For making up the preparations there can beemployed substances which do not react with the new compounds, such aswater, gelatine, lactose, starches, stearic acid, magnesium stearate,stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes,propylene glycol, polyalkylene glycols or any other known carrier formedicaments. The pharmaceutical preparations may be in solid form, forexample, as capsules, tablets or dragees, or in liquid form, forexample, as solutions, sus: pensions or emulsions. If desired, they maycontain auxiliary substances such as preserving agents, stabilizingagents, wetting or emulsifying agents, salts for varying the osmoticpressure or buffers. They may also contain, in combination, othertherapeutically useful substances.

The compounds of this invention are advantageously prepare-d by reactingan aniline compound of the formula Rz'-HNO2S SOzNI-I-Rz R3 NH 1&2]!

in which R R R and R have the previously-given meaning, with an aldehydeof the formula R CHO, in which R has the above-given meaning, or areactive derivative thereof, and, if desired, converting a resultingsalt into the free compound, and/ or, if desired, converting a resultingfree compound into a salt thereof.

The reaction may be performed in the absence of any condensing reagent,or in the pre:ence of a base, such as an alkali metal hydroxide, e.g.lithium hydroxide, sodium hydroxide, potassium hydroxide and the like,whereby the aldehyde is used in its reactive form. It may also becarried out in the presence of a small amount of an acid, for example, amineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and thelike, if desired, in anhydrous form. The presence of an acid may headvantageous, whenever the aldehyde is employed in the form of areactive derivative thereof. For example, aldehydes may be given to thereaction medium in a form which yields the desired reactant in situ.Thus, an acetal of an aldehyde R -CHO with a lower alkanol, e.g.methanol, ethanol and the like, or an alkali metal, e.g. sodium orpotassium, bisulfite addition compound is advantageously used in thepresence of a mineral acid. Alkali metal bisulfite addition compoundsare, for example, the sodium bisulfite addition compounds ofcyclopentylacetaldehyde, 3-cyclopentyl-propionaldehyde and the like;reactive acetals are, for example, cyclopropane carbox-aldehyde diethylacetal (cyclopropyl-diethoxy-methane), cyclobutane carboxaldehydediethyl acetal (cyclobutyldiethoxy-methane), cyclopentane carboxyalehydedimethyl acetal (cyclopentyl-dimethoxy-methane), cyclopentanecarboxaldehyde diethyl acetal (cyclopentyl-diethoxymethane), cyclohexanecarboxaldehyde diethyl acetal (cyclohexyl-diethoxy-methane),cycloheptane carboxaldehyde (cycloptyl-diethoxy-methane), cyclooctanecarboxaldehyde diethyl acetal (cyclooctyl-diethoxy-methane),3-cyclohexene carboxaldehyde diethyl acetal(Ii-cyclohexenyl-diethoxy-methane), cyclopentyl-acetaldehyde diethylacetal (l-cyclopentyl-2,2-diethoxy-ethane), cyclohexylacetaldehydediet-hylacetal (1 cyclohexyl 2,2-diethoxy-ethane),2-(3-cyclohexenyl)-acetaldehyde diethyl acetal(l-[3-cyclohexenyl]-2,2-diethoxy-ethane) and the like.

The reaction may preferably be carried out in the presence of a solvent,for example, an .ether, e.g. tetrahydrofuran, p-dioxane,diethyleneglycol dimethylether and the like, a lower alkanol, e.g.methanol, ethanol and the like,

or a formamide, e.g. dimethylformamide and the like, a

lower alkanone, e.g. acetone and the like, a mixture of such solvents,an aqueous mixture of such solvents or water, or any other suitablediluent. If desired, it may be completed at an elevated temperature, forexample, by heating on a steam bath or at the boiling temperature of thesolvent. If necessary, the reaction may be per formed under increasedpressure or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials'used in the above-described reactions are known,of, if new, may be prepared according to procedures used for themanufacture of known compounds. For example, by treatment of a 3-R -N-Raniline, in which R and R have the above-given meaning withchlorosulfonic' acid, two sulfonyl chloride groups are introduced toform 5-R -N-R "-aniline-2,4-disulfonyl chlorides. These are subsequentlyreacted with ammonia, e.g. liquid or gaseous ammonia, or with a solutionof ammonia in water or in a lower alkanol, methanol or ethanol, or withan N-lower alkylamine, e.g. N-methylamine, N-ethylamine and the like, toyield the desired starting materials of the above-mentioned type. Thesulfamyl groups of the starting material may also be introduced instages; for example, one of the sulfonyl chloride groups may beconverted to a sulfamyl group with ammonia or an N-lower alkyl-amine bycontrolling the reaction as to amounts of the reactants and/ or thereaction conditions, and the second sulfonyl chloride group may then beconverted to the desired sulfamyl group. The acetals of the'aldehydeswith lower alkanols, e.g. ethanol and the like, may be prepared, forexample, by reacting a carbocyclic aliphatic hydrocarbon or acarbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon halide,e.g. chloride, bromide, iodide, and the like, with magnesium, treatingthe resulting Grignard reagent with a lower alkyl ester of orthoformicacid, e.g. methyl orthoformate, or particularly ethyl orthoformate andthe like, and isolating the desired carbocyclic aliphatic hydrocarboncarboxaldehyde lower alkyl acetal or the carbocyclic aliphatichydrocarbon-lower aliphatic hydrocarbon carboxaldehyde lower alkylacetal.

A second procedure for the preparation of compounds of this inventioncomprises removing in compounds of the formulae in which R R R and Rhave the previously-given meaning, the C=N double bond of thel,*2,4-thiadiazinel,l-dioxide portion by reduction, and, if desired,carrying out the optional steps.

The removal of the O=N-- double bond may be achieved, for example, bytreatment with a borohydride or an equivalent reducing agent capable ofremoving such double bond. The preferred reagents are alkali metalborohydrides, e.g. lithium borohydride, potassium borohydride or,particularly sodium borohydride. Other borohydrides are alkaline earthmetal borohydrides such as calcium or strontium borohydride; aluminumborohydride may be used as well, and sodium dimethoxy borohydride isanother possible reducing reagent. If desired, these borohydrides may beused in the presence of an activating substance, such as, for example,aluminum chloride. The reaction may also be carried out in the presenceof an alkaline reagent, such as an aqueous alkaline reagent, which maybe diluted with other solvents,

such as those mentioned hereinbelow; alkaline reagents are, for example,dilute aqueous solutions of alkali metal hydroxide, e.g. lithium, sodiumor potassium hydroxide. If desired, organic solvents, such as ethers,e.g. 1,2-dimethoxyethane, diethyleneglycol dimethylether and the like,lower alkanols, e.g. methanol, ethanol, propanol, isopropanol and thelike, or liquid carboxylic acid amides, such as formamides, e.g.formamide, N,N-dimethylformamide and the like, may be employed. Thereduction is carried out at room temperature or at an elevatedtemperature, if necessary, in the atmosphere of an inert gas, such asnitrogen.

Catalytic reduction under certain conditions may also be used for theremoval of the O=N- double bond. For example, treatment of the startingmaterial, particularly a solution thereof, with hydrogen in the presenceof a catalyst containing a metal of the eighth group of the PeriodicSystem, and of an organic base, may cause the removal of the doublebond. Suitable solvents are, for example, lower alkanols, e.g. methanol,ethanol and the like, ethers, e.g. diethyleneglycol dimethylether andthe like, or other equivalent solvents. Metals of the eighth group ofthe Periodic System, present in the catalysts, may be, for example,palladium, platinum and the like; these metals may be supported byadsorbents, such as charcoal, aluminum oxide, silicagel and the like.Palladium on charcoal, platinum oxide and the like may serve ascatalysts. An organic base is particularly a heterocyclic basiccompound, particularly an N,N-alkyleneimine, e.g. pyrrolidine,piperidine and the like, or an N,N-aza-alkyleneimine, e.g. piperazineand the like, or any other suitable base. The hydrogenation may becarried out under atmospheric or under increased pressure, if necessary,while heating.

The electrolytic reduction procedure provides for another possibility ofremoving the C=N double bond; such procedure is carried out according tostandard methods. Generally, it is performed on a cathode of highoverpotential and at a current density greater than about 0.02.amps./cm. Cathodes with high overpotentials are, for example, thosehaving an overpotential equal to or higher than cadmium, such ascadmium, zinc, mercury, lead amalgam or lead. Any appropriate anode,such as platinum, carbon, lead or stainless steel, and any appropriateanolyte, for example, dilute sulfuric acid or dilute hydrochloric acid,may be employed. A lead or a platinum anode and a dilute sulfuric acidanolyte are preferred.

A current density greater than about 0.02 amps/cm. is sufficient tobring about the reduction of the C=N double bond; however, for practicalreasons a current density higher than about 0.25 amps/cm. may diminishthe efficiency of the process due to increased hydrogen evolution.

The reduction is performed in an aqueous acidic medium, such as, forexample, an aqueous solution of a strong inorganic acid, which ionizesreadily and does not decompose at the current density employed, such as,for example, sulfuric acid. In order to secure a complete solution ofthe starting material in additional solvent, such as, for example, aformamide, e.g. N,N-dimethyl-formamide and the like, may be added. Loweralkanols, e.g. methanol, ethanol and the like, may replace or may 'beadded with a formamide to enhance the solubility of the startingmaterial and the end product.

Diaphragms separating the anolyte and the catholyte are more especiallyion exchange membranes, such as ion exchange resins (amberplex), alundumof parchment and the like.

Any groups, which may be affected by the hydrogenation procedure, may beprotected or simultaneously converted into hydrogenated groups.

The starting materials used in this reaction are known, or, if new, maybe obtained according to procedures used for the preparation of theknown compounds.

In resulting 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-

dioxides, containing sulfamyl-nitrogen atoms carrying hydrogen, suchhydrogen may be replaced by aliphatic hydrocarbon radicals, such aslower alkyl, particularly lower alkyl containing from one to four carbonatoms, e.g. methyl, ethyl and the like, or lower alkenyl, particularlyallylic lower alkenyl containing from three to five carbon atoms, e.g.allyl, Z-methyl-allyl, but-Z-enyl and the like, or carbocyclicaryl-lower aliphatic hydrocarbon, such as monocyclic carbocyclicaryl-lower alkyl, particularly phenyl-lower alkyl, in which lower alkylcontains from one to four carbon atoms, e.g. benzyl, l-phenylethyl,2-phenylethyl and the like. Generally, an alkali metal salt of thestarting material is formed and such salt is then reacted with thereactive ester formed by an aliphatic hydrocarbon alcohol or acarbocyclic aryl-lower aliphatic hydrocarbon alcohol and strong mineralacids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and thelike. For example, treatment of the starting material with a di-loweralkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, inthe presence of an alkaline reagent, such as an alkali metal hydroxide,e.g. lithium, sodium or potassium hydroxide, represents a procedure forintroducing lower alkyl radicals. As solvents, water or water miscibleorganic solvents, such as lower alkanols, e.g. methanol, ethanol,propanol, isopropanol, tertiary butanol and the like, ethers, e.g.diethyleneglycol di methylether and the like, or formamides, e.g.N,N-dimethyl-formamide and the like, may be used.

Or, an alkali metal, e.g. lithium, sodium or potassium, salt of thestarting material, prepared by treating the latter with an alkali metal,e.g. lithium, sodium or potassium, hydride, amide or hydroxide may bereacted With a lower alkyl halide, e.g. methyl or ethyl chloride,bromide or iodide and the like, a lower alkenyl halide, e.g. allylchloride, bromide or iodide and the like, or a phenyllower alkyl halide,e.g. benzyl or Z-phenylethyl chloride, bromide or iodide and the like.Diluents are primarily those previously mentioned and are chosen inaccordance with their inertness towards the reactants and the solubilityof the latter.

Generally, the above reaction is carried out under cooling, particularlyif a di-lower alkyl sulfate is employed, at room temperature, or at anelevated temperature, and, if necessary, it is performed in a closedvessel, e.g. sealed tube, under pressure and/ or in the atmosphere of aninert gas, e.g. nitrogen.

An N-unsubstituted sulfamyl group attached to the 7- position of themolecule may react simultaneously with the reactive ester. If necessary,this may be prevented to a large extent by varying the conditions and/or the molar ratios of the reactants. A resulting mixture of productsmay be separated into the single components, for example, byfractionated crystallization, utilizing the differing solubilities indifferent solvent systems.

The resulting product may be obtained in the form of the 'free compoundor as a salt thereof. An alkali metal salt may be converted into thefree compound by treatment with an aqueous acidic reagent, such as amineral acid, e.g. hydrochloric, sulfuric acid and the like. A freecompound may be converted into an alkali metal salt, for example, bytreatment with an alkali metal hydroxide, e.g. sodium hydroxide,potassium hydroxide and the like, in a solvent, such as in a loweralkanol, e.g. methanol or ethanol, or in water and evaporating thesolvent; or by reacting the free compound, for example, in an ether,e.g. p-dioxane or diethyleneglycol dimethyl-ether, solution, with analkali metal hydride or amide, e.g. sodium or potassium hydride oramide, and removing the solvent. Monoor poly-salts may be obtained.

Any resulting racemate may be converted into the antipodes thereofaccording to methods used for resolving racemates.

The following examples illustrate the invention; they are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centigrade.

Example 1 A mixture of 5.7 g. of -chloro-2,4-disulfarnyl-aniline, 2,2 g.of 3-cyclohexene carboxaldehyde and 1 ml. of ethyl acetate saturatedWith hydrogen chloride in 50 ml. of diethylene glycol dimethylether isheated on the steam bath for one hour. Two thirds of the solvent isstripped off under reduced pressure; the residue is added to water Whilestirring. The crystalline6-chloro-3-(3-cyclohexenyl)-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine1, l-dioxide is collected and recrystallized from methanol, M.P.252-254".

In the above reaction, 5-chloro-2,4-disulfamyl-aniline may be replacedby 5-bromo-2,4'disulfamyl-aniline or 2,4-disulfamyl-5-trifluoromethyl-aniline; when reacted with 3-cyclohexenecarboxaldehyde as mentioned hereinabove, these aniline derivatives yield6-bromo-3-(3-cyclohexenyl)-7-sulfamyl-3,4-dihydro-2H-1,2,4benzothiadiazine- 1,1-dioxide or 3-(3-cyclohexenyl-7-sulfamyl-6-trifluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide.

Example 2 A mixture of 6.2 g. of cyclopentyl-diethoxy-methane (diethylacetal of cyclopentane carboxaldehyde), 7.4 g. of5-chloro'2,4-disulfamyl-aniline, S-ml. of diethyleneglycol dimethyletherand 2 ml. of concentrated hydrochloric acid is heated on the steam bathfor two hours. Upon cooling a crystalline precipitate is formed, whichis collected and washed with ethanol. The 3-cyclopentyl- 6 chloro 7sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-Ll-dioxide melts at271272.

The 5-chloro-2,4-disfulfamyl-amine may be replaced by2,4-disulfamyl-S-trifluoromethyl-aniline and reacted with the diethylacetal of cyclopentane carboxaldehyde to yield the desired3-cyclopentyl-7-sulfamyl-6-trifluorornethyl-3,4-dihy'dro-2H-1,2,4-benZothiadiaZine-1 ,l-dioxide.

The cyclopentyl-diethoxy-methane (diethyl acetal of cyclopentanecarboxaldehyde) used as the starting material may be prepared asfollows: To a mixture of 20 g. of bromocyclopentane and 3.26 g. ofmagnesium turnings in ether is added one crystal of iodine; the mixtureis refluxed until the magnesium has disappeared and is then cooled. 15.9g. of ethyl orthoformate is given to the Grignard reagent, the reactionmixture is refluxed for sixteen hours and is then chilled. 79.5 g. of 6percent aqueous hydrochloric acid is added dropwise while stirring andcooling. A yellow oil separates, which is dissolved in additional ether;the organic layer is separated, washed with water and dried over sodiumsulfate. The solvent is evaporated and the crudecyclopentyl-diethoxy-methane (diethyl acetal of cyclopentanecarboxaldehyde) is used without further purification,

' Example 3 A mixture of 5.0 g. of the cyclohexyl-diethoxy-methane(diethyl acetal of cyclohexane carboxaldehyde), 5.7 g. of5-cl1loro-2,4-disulfamyl-aniline, 20 ml. of diethyleneglycoldimethylether and 2 ml. of concentrated hydrochloric acid is heated at95 for three hours. The desired 6 chloro3-cyclohexyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide precipitates and is collected; M.P. 278280.

An aqueous solution of the sodium salt of 6-chloro-3- cyclohexyl 7sulfamyl 3,4 dihydro 2H 1,2,4- benzothiadiazine-1,1-dioxide may beobtained by dissolving6-chloro-3-cyclohexyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiaZine-1,l-dioxide in an equivalent amount of 2N aqueoussodium hydroxide solution.

The starting material may be prepared as shown in Example 2, Le. theGrignard reagent formed from bromocyclohexane and magnesium is treatedwith ethyl orthoformate and the desired cyclohexyl-diethoxy-methane(diethyl acetal of cyclohexane carboxaldehyde) is used without furtherpurification.

Other compounds prepared according to the above procedure by selectingthe appropriate starting materials are, for example, 6 chloro3-cyclopropyl-7-sulfamyl-3, 4 dihydro 2H1,2,4-benzothiadiazine-1,l-dioxide, 6- chloro 3 cyclobutyl7-sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1 dioxide,6-chloro-3cycloheptyl- 7 sulfamyl 3,4dihydro-2H-1,2,4-benzothiadiaZine-1, l-dioxide, 6 chloro 3cyclooctyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxideand the like.

Example 4 A mixture of 1.0 g. of cyclopentyl-acetalclehyde, 2.6 g. of5-chlor0-2,4-disulfamyl-aniline, 1 ml. of a concentrated solution ofhydrogen chloride in ethyl acetate and 15 ml. of diethyleneglycoldimethylether is heated on the steam bath for 2 /2 to 3 hours and thenallowed to stand overnight. The solution is concentrated to a smallvolume, the residue is poured into Water while stirring and theresulting precipitate is filtered off. The 6-cholo-3-cyclopentylmethyl 7sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide isrecrystallized from a mixture of ethanol and water, M.P. 230-231".

The aldehyde used as the starting material may be prepared, for example,by converting cyclopentyl-acetic acid into its chloride and treating thelatter with hydrogen in the presence of palladium on barium sulfate as acatalyst according to the Rosenmund procedure.

Other 3,4 dihydro 2H 1,2,4-benzothiadiazine-1,1- dioxides, which may bemanufactured according to the previously-given procedure by varying thestarting materials, are 6-chloro 3 cyclopropylmethyl-7-sulfamyl-3, 4dihydro 2H 1,2,4-benzothiadiazine-l,l-dioxide, 6- chloro 3 (3cyclohexenylmethyl)-7-sulfamyl-3,4-dihydro 2H1,2,4-benzothiadiazine-1,l-dioxide. 6-bromo- 3 cyclopentylmethyl 7sulfamyl3,4-dihydro-2H-1,2, 4 benzothiadiazine 1,1-dioxide,3-cyclopentylmethyl-7- sulfamyl 6trifluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine'l,l-dioxide,6-chloro-3 (2-cyclohexylethyl)- 7 sulfamyl3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide and the like.

Example 5 By treating a solution of 6-chlor0-3-(3-cyclohexenyl)- 7sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide in aqueoussodium hydroxide with dimethyl sulfate at 10 and then at roomtemperature a mixture of the 6 chloro 3(3-cyclohexenyl)-2-methyl-7-sulfamyl-3, 4 dihydro2H-1,2,4-benzothiadiazine-1,l-dioxide and 6 chloro 3(3-cyclohexenyl)-2-methyl-7-(N-methylsulfamyl) 3,4dihydro-2H-1,2,4-benzothiadiaZine-1,ldioxide which can be separated intothe two components by fractionated crystallization.

Example 6 By treating a solution of 6-chloro-3-(2-cyclopentylethyl) 7sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in diethyleneglycoldimethylether with sodium borohydride at room temperature for tWo hours,concentrating the solution and adding water to the residue, the6-chloro-3-(2- cyclopentylethyl) 7 sulfamyl 3,4-dlihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide may be obtained.

The starting material used in the above reaction may be prepared byreacting 5-chloro-aniline-2,4-disulfonyl chloride with3-cyclopentyl-propionyl chloride, treating the resulting 5 chloroN(3-cyclopentylpropionyl)-aniline- 2,4-disulfonyl chloride with ammoniaand subsequently heating the resulting product to achieve ring closureto the desired 6 chloro 3(2-cyclopentyl-ethyl)-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide.

The above described 6-chloro-3-(Z-cyclopentylethyl)-7-sulfamyl-3,4-dihydro-2H 1,2,4 benzothiadiazine-Ll-dioxide may also beprepared by treating 5-chloro-2,4-disulfamyl-aniline with3-cyclopentyl-propionaldehyde or a reactive functional derivativethereof, such as an acetal or ing to the method described in Example 4.

Example 7 To a solution of 24.5 g. of the cyclopentylacetaldehyde sodiumbisulfite addition compound in 17 ml. of water and 110 ml. ofconcentrated hydrochloric acid is added 31.2 g. of-chloro-2,4-disulfamyl-aniline and 250 ml. of ethanol; the mixture isrefluxed for four hours on the steam bath and then filtered hot. Uponchilling, a crystalline precipitate is formed, which is filtered off andrecrystallized from a mixture of ethanol and water to yield the pure6chloro-3-cyclopentylmethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,MP. 238- 240". The product is identical with the compound obtainedaccording to the process of Example 4.

The above obtained 6-chloro-3-cyclopentylmethyl-7- sulfamyl-3,4-dihydro2H-l,2,4 benzothiadiazine-1,1-dioxide may also be prepared, for example,by treating a solution of 6-chloro-3-cyclopentylmethyl-7-sulfamyl-1,2,4-benzothiadiazined,l-dioxide (prepared fromS-chloroaniline-2,4-disulfonyl chloride, by reacting the latter withcyclopentyl-acetyl chloride and treating the resulting 5-chloro-N-cyclopentylacetyl-aniline-2,4-disulfonyl chloride with ammoniato form the sulfamyl derivative with simultaneous ring closure) inethanol containing a small amount of aqueous sodium hydroxide withsodium borohydride.

Generally, 6-chloro-3-cyclopentylmethyl 7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 dioxide or an alkali metalsalt thereof may be prepared by reacting 5-chloro-2,4-disulfamyl-aniline with cyclopentylacetaldehyde or a reactivefunctional derivative thereof, such as an acetal thereof, e.g. dimethylacetal, diethyl acetal and the like, or the sodium bisulfite additioncompound thereof, or reducing in6-chloro-3-cyclopentylmethyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide the C=N double bond in theheterocyclic portion of the 1,2,4-benzothiadiazine-1,1-dioxide nucleus,and, if desired, converting a resulting salt into the free compound,and/ or, if desired, converting the free compound into a salt thereof.These reactions are carried out according to the previously describedprocedures.

Example 8 A mixture of 2.5 g. of cyclohexyl-acetaldehyde, 5.8 g. of5-chloro-2,4-disulfamyl-aniline, 50 ml. of diethyleneglycoldimethylether and 3 ml. of a saturated solution of hydrogen chloride inethyl acetate is heated on the steam bath for three hours. The solutionis evaporated to a small volume, the residue is poured into water,triturated and allowed to stand for several hours. The crystallinematerial is filtered olf and recrystallized from a 9: l-mixture ofethanol and water to yield the6-chloro-3-cyclohexylmethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4benzothiadiazine-1,1- dioxide, M.P. 224226; yield: 6.0 g.

The aldehyde used in the above preparation can be prepared according tothe Rosenmund procedure as follows: A slow stream of hydrogen is passedthrough a mixture of 2.0 g. of palladium on barium sulfate (containing 5percent palladium), 0.5 ml. of a solution of quinoline and sulfur inxylene (prepared by refluxing 8.5 g. of freshly distilled quinoline and1.4 g. of sulfur for five hours, and diluting the mixture with xylene toa total volume of 99 ml.), and 125 ml. of xylene; about 10 ml. of thesolvent is distilled off to remove any trace of water. 19.3 g. ofcyclohexyl-acetic acid chloride is added; the reaction mixture is heatedby keeping a bath temperature of 190-195 and a slow stream of hydrogenis passed through the mixture while stirring. The evolved hydrogenchloride is collected and titrated at intervals to determine the endpoint of the reduction. Treatment with hydrogen is terminated after 11/2 hours (90 percent of the theoretical amount of hydrogen chloride hasbeen generated), the reaction mixture is cooled, the catalyst isfiltered off and the filtrate is diluted with 300 ml. of diethyl ether.The organic solution is diluted with 400 ml. of saturated aqueous sodiumbisulfite and stirred for seventeen hours. The solid sodium bisulfiteaddition compound of the 12 cyclohexyl-acetaldehyde is filtered off andWashed with diethyl ether, yield: 28 g. The solid material is stirredwith 30 ml. of a 20 percent aqueous solution of sodium carbonate untilit dissolves. The organic material is extracted with diethyl ether, theorganic layer is dried and evaporated to give 3.0 g. of crudecyclohexylacetaldehyde.

The following compounds may also be prepared according to the abovemethods by selecting the appropriate starting materials, whereby thealdehydes may be used as such or in the form of reactive derivatives,i.e., acetals, e.g. dimethyl acetal, diethyl acetal and the like, orsodium bisulfite addition compounds:

6-chloro-3-( l-cyclopentylethyl) -7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3-cyclobutylmethyl-7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3 l-cyclobutylethyl -7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3 2-cyclopentenylmethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3 -[2(1-cyclopentenyl)-ethyl]-7-sulfamyl-3,4-

dihydro-ZH- 1 ,2,4-benzothiadiazine- 1 l-dioxide,

6-chloro-3-[1-(2-cyclopentenyl)-ethyl]-7-sulfamyl-3,4-

dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3-( l-cyclohexylethyl) -7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,

6-chloro-3-( l-cyclohexylethyl -7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3-[3-cyclohexenyl) -ethyl] -3,4-dihydro-2H-1,2,4-

benzothiadiazine- 1 1 -dioxide,

6-chloro-3-cycloheptylmethyl-7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benz0thiadiaZine-l, l-dioxide,

6-chloro-3 2-cycloheptenylmethyl -7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chlor0-3-cyclo-octylmethyl-7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide, and the like.

In the above-described compounds with carbocyclic alicyclic hydrocarbonradicals containing double bonds in the 3-position, the latter may beconverted into saturated carbocyclic alicyclic hydrocarbon radicals byreduction. The reduction may be achieved for example, by treatment of aliquid ammonia solution of the compound containing an unsaturatedcarbocyclic alicyclic hydrocarbon radical with an alkali metal,particularly lithium and the like. Catalytic reduction may also be used,but care has to be taken that the carbocyclic aryl portion of thebenzothiadiazine ring system or any other groups, e.g. halogen and thelike, are not affected; treatment with hydrogen in the presence of Raneynickel, using a lower alkanol, e.g. ethanol and the like, as a solvent,may be feasible.

What is claimed is:

1. A member of the group consisting of compounds of the formula in whichR represents cycloalkyl having from three to eight ring carbon atoms andR stands for trifluoromethyl, and alkali metal salts thereof.

2. 6 trifluoromethyl 3 cyclopentyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide.

3. 6 trifluoromethyl 3 cyclohexyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadizine-1,l-dioxide.

4. A member of the group consisting of compounds of the formula in whichR represents cycloalkenyl having from four to eight ring carbon atoms,and R stands for trifluoromethyl, and alkali metal salts thereof.

5. 6 trifluoromethyl 3 (2 cyclopentenyl)-7-sulfamyl 3,4 dihydro2H-1,2,4'benzothiadiazine-1,1-dioxide.

6. 6 trifiuoromethyl 3 (3 cyc1ohexenyl)-7-sulfamyl 3,4 dihydro2H-1,2,4-benzothiadiazine-1,1-dioxide.

7. A member of the group consisting of compounds of the formula in whichR represents cycloalkyl-lower alkyl, in which cycloalkyl has from threeto eight ring carbon atoms and lower alkyl has from one to four carbonatoms, and R stands for trifluoromethyl, and alkali metal salts thereof.

8. 6 trifluoromethyl 3 cycloalkyl-lower alkyl-7- sulfamyl 3,4dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide, in which cycloalkyl hasfrom five to six ring carbon atoms and lower alkyl has from one to twocarbon atoms.

9. 6 trifiuoromethyl 3 cyclopentylmethyl-7-sulfamyl 3,4 dihydro2H-l,2,4-benzothiadiaZine-1,l-dioxide.

10. 6 trifiuoromethyl 3 (1-cyclopentylethyl)-7- sulfamyl 3,4 dihydro2H-1,2,4-benzothiadiazine-1,1- dioxide.

11. 6 trifiuoromethyl 3 (2 cycIopentylethyl)-7- sulfamyl 3,4 dihydroZH-l,2,4 benzothiadiazine-l,1- dioxide.

12. 6 trifluoromethyl 3 cyclohexylmethyl 7-sulfamyl 3,4 dihydro 2H1,2,4-benzothiadiazine-1,1- dioxide.

13. A member of the group consisting of compounds of the formula inwhich R represents cycloalkenyl-lower alkyl, in which cycloalkenyl hasfrom four to eight ring carbon atoms, and lower alkyl has from one tofour carbon atoms, and R stands for trifiuo' romethyl and alkali metalssalts thereof.

14. 6 trifluoromethyl 3 cycloalkenyl-lower alkyl- 7-sulfamyl-3,4-dihydro2H 1,2,4 tbenzothiadiazine-Lldioxide, in which cycloalkenyl has fromfive to six carbon atoms, and lower alkyl has from one to two carbonatoms.

15. 6-trifluoromethy1 3 (2-cycl0pentenylmethyl)-7- sulfamyl 3,4 dihydro2H-l,2,4-benzothiadiazine-1,1- dioxide.

16. 6-trifluoromethyl 3 [2-(1-cyclopentyl)-ethyl-7- sulfamyl 3,4dihydro-ZH-l,2,4-benzothiadiazine-1,1-dioxide.

17. A compound of the formula and an alkali metal salt thereof, whereinn is selected from the group consisting of zero and one; and R isselected from the group consisting of cycloalkyl of four to seven carbonatoms, cyclopentenyl, cyclohexenyl and cycloheptenyl.

References Cited UNITED STATES PATENTS 3,163,644 12/1964 de Stevens etal. 260243 NICHOLAS S. RIZZO, Primary Examiner. IRVING MARCUS, Examiner,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,351,595 November 7, 1967 George de Stevens et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 2, line 49, "3(3-cyclo-" should read 3- (3- cyclo- Column 6 line9 f" hould read or Column 9, line 2, "2,2" should read 2.2 line 31,"disfulfamyl-amine" should read disulfamyl-aniline Column 10, line 6,"6-ch1oro-3 cyclooctyl" should read 6-chloro-3-cyclooctyl Column 13,lines 15 to 20, the formula should appear as shown below:

2 H NO S NH RT- l Column 14, line 22, "ethyl" should read ethyl] Signedand sealed this 20th day of January 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR

EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer

1. A MEMBER OF THE GROUP CONSISTING OF THE FORMULA